Neurostructural subgroup in 4291 individuals with schizophrenia identified using the subtype and stage inference algorithm

Machine learning can be used to define subtypes of psychiatric conditions based on shared biological foundations of mental disorders. Here we analyzed cross-sectional brain images from 4,222 individuals with schizophrenia and 7038 healthy subjects pooled across 41 international cohorts from the ENIGMA, non-ENIGMA cohorts and public datasets. Using the Subtype and Stage Inference (SuStaIn) algorithm, we identify two distinct neurostructural subgroups by mapping the spatial and temporal ‘trajectory’ of gray matter change in schizophrenia. Subgroup 1 was characterized by an early cortical-predominant loss with enlarged striatum, whereas subgroup 2 displayed an early subcortical-predominant loss in the hippocampus, striatum and other subcortical regions. We confirmed the reproducibility of the two neurostructural subtypes across various sample sites, including Europe, North America and East Asia. This imaging-based taxonomy holds the potential to identify individuals with shared neurobiological attributes, thereby suggesting the viability of redefining existing disorder constructs based on biological factors.


Assumptions about schizophrenia for SuStaIn
In our modelling approach, we assume that disease progression is a linear deviation from the normality of a patient's brain profile.In this context, it is important to distinguish anatomical progression from clinical progression.Concerning positive symptoms, progressive deviation from normality does not occur in schizophrenia.Most patients show a degree of symptomatic amelioration over a long time, despite recurrent periods of exacerbation [1].Concerning negative symptoms, despite some early improvement, a cumulative pattern with pronounced deficits is seen in several patients receiving psychiatric care [2].Concerning the grey matter volume, when cross-sectional studies across various illness stages are considered, a pattern of spatial expansion of structural changes, as well as an increase in magnitude (effect size) of localized changes are noted.A subtle increase in grey matter is also a feature of schizophrenia, and this increase may appear in the early stages [3,4].To date, such subtle increases have not been shown to 'reverse' the early grey matter reduction to the point of return to normality [5].Thus, the assumption that a lack of atrophy reflects the earliest stages of illness, while progressively later stages show more deviation from normality is thus reasonable based on the extant literature on structural changes in schizophrenia.
We also assume that tonic changes rather than event-related changes (relapse) occur in schizophrenia.There are not many empirical data to directly address this question, but the amount of time spent in a symptomatic state, rather than the number of relapses, has a direct relationship to grey matter reduction in the presence of psychosis [6,7].As residual symptom burden is the norm rather than an exception in the schizophrenia [8], tonic changes in grey matter volume are a reasonable expectation, though the rate of this change may vary with the stage of illness.
When interpreting our modelling approach, it is worth noting that the presence of pre-onset neurodevelopmental brain abnormalities per se does not preclude a specific post-onset pattern of disease progression.The model we apply is agnostic as to the origins of the structural deficits seen at the onset; in other words, the model considers baseline deficits (e.g., insular volume reduction in subtype1) to have resulted from multiple processes (including neurodevelopmental deviation) but allows for the same pattern of deficits (i.e., insular volume loss) to occur later in the illness via putative degenerative or compensatory pathways in the subtype2.As a result, the assumptions required to interpret our model to accommodate pre-existing, putatively developmental, structural deficits.Similar to dementias, no brain region is known to consistently display higher grey matter volume at later stages compared to earlier stages of schizophrenia to date (in adults) (for example, see Koutsouleris et al. [9]).When we consider individualized centile scores for grey matter volume in the context of normative age-related trends [10]: schizophrenia closely follows Alzheimer's disease, with volume reduction in schizophrenia being more pronounced than in mild cognitive impairment (MCI).Thus, while we apply a modelling approach (SuStaIn) that is mostly used for the neurodegenerative condition, the similarities in the spatiotemporal patterns of structural changes between dementias and schizophrenia allow us to translate the model to a nondegenerative condition.The inclusion/exclusion criteria of healthy subjects in two samples were identical to those of the patient group except that they did not meet the DSM-IV diagnostic criteria of any mental disorders screened using the SCID non-patient version.We also ensured that for healthy subjects, no firstdegree relatives had a history of any psychiatric disorders.(could be increased to 18 cm when needed for full brain coverage).controls and patients were included in the study provided that the duration of their medication did not exceed 2 months of lifetime use and no medication was used within the 6 months preceding the baseline MRI scan.
Control subjects who met criteria for current or past history of substance abuse or dependence were excluded from the study.Patients, however, were not excluded from the study unless criteria were met for current (i.e., within the past month) abuse or dependence (except for 6 patients who were found to meet criteria for current abuse after the study data was collected).Both patients and controls were excluded if they had (1)  The individuals with schizophrenia were all outpatients, and were stabilized on antipsychotic medication for at least 2 weeks.Controls were required to have no lifetime history of Axis I psychotic or mood disorders and no first-degree relatives with a psychotic disorder.Healthy controls met the same exclusion criteria as the patients, and they were also interviewed using the SCID to exclude current and past psychiatric disorders.They were questioned and excluded if they reported a history of treatment with psychotropic medication beyond non-habitual use of night sedation.Controls were also excluded if they reported a history of major psychiatric disorder in a first-degree relative.Supplementary Table 3. Demographic and clinical characteristics of participants in the first-episode subsample and medication-naive subsample.

5 Schizophrenia:( 1 )
sagittal slices, 320x274 matrix size, .75mmisotropic, TR = 11ms, TE=4.562ms, flip angle = 18° UNINA DSM-Diagnosis of SZ (Patients); (2) Age: 18-60; (3) Provision of informed written consent; (4) Disease duration >2 years; (5) no medication switch or dose changes in the last 6months (i.e., >10% baseline dose);(6) no evidence of current or recent (3 months) worsening of psychotic symptoms; absence of:(7) macroscopic brain structural anomalies; (8) major systemic disorder (such as cardiovascular, endocrine, metabolic disorders); (9) other psychiatric disorder (including addiction disorder, substance use disorder, or frequent substance use in the 6 months preceding the recruitment); (10) moderate or severe neurological disorder; (11) intellectual disability; (12) pregnancy or lactation; (13) enrollment in any sort of experimental clinical trial within 3 months 3T Siemens Tim Trio 3D T1-weighted Magnetization Prepared Rapid Acquisition Gradient Echo sequence (MPRAGE; TR=1900 ms; TE=3.4 ms; TI=900 ms; Flip Angle=9°; resolution=1x1x1 mm3; 160 axial slices).from recruitment.Controls:(1) No psychiatric diagnosis; (2) Age: 18-60; (3) Provision of informed written consent; 4) Absence of: macroscopic brain structural anomalies; major systemic disorder (such as cardiovascular, endocrine, metabolic disorders); moderate or severe neurological disorder; intellectual disability; pregnancy or lactation Zurich MINI DSM IV A diagnosis of schizophrenia.We excluded patients with any other DSM-IV Axis I disorder (in particular, current substance use disorder and major depressive disorder), those medicated with lorazepam at a dose higher than 1 mg, those with florid psychotic symptoms (i.e., any positive subscale item scores higher than 4 on the PANSS scale and those with extrapyramidal side effects (i.e., a total score higher than 2 on the MSAS).Healthy controls were screened for any neuropsychiatric disorders using the structured Mini-International Neuropsychiatric Interview to ensure that they had no previous or present psychiatric illness.Both patients and healthy controls were required to have a normal physical and neurologic status and no history of major head injury or neurologic disorder.3T Philips 3D T1-weighted images were acquired with an ultra-fast gradient echo T1weighted sequence (TR=8.4ms,TE=3.8ms, flip angle=8°) in 160 sagittal plan slices (1mm slice thickness, no slice gap) of 240×240mm2 resulting in 1x1x1mm3voxelsin the 18-65 age range and had a diagnosis of schizophrenia.Healthy individuals were included if they did not have a personal or family history of psychiatric disorders.History of neurological disorder, history of mental retardation, history of severe head trauma with more than 5 minutes loss of consciousness, history of substance abuse or dependence within the last 12 months and MRI contraindications.3T Siemens TIM Trio T1-weighted images were acquired with a 5-echo multi-echo MPRAGE sequence [TE (echo times) = 1.64, 3.5, 5.36, 7.22, 9.08 ms, TR (repetition time) = 2.53 s, TI (inversion time) = 1.2 s, 7° flip angle, number of excitations (NEX) = 1, slice thickness = 1 mm, FOV (field of view) = 256 mm, resolution = 256x256].TOPSY DSM-V Inclusion criteria for FEP: individuals experiencing FEP, with lifetime antipsychotic treatment less than 14 days.Exclusion criteria for FEP: meeting criteria for a mood disorder (bipolar or major depressive) with psychotic features, or possible drug-induced psychosis.Healthy control (HC) participants were free from personal history of mental illness or family history of psychotic disorders, matched based on age, sex, and parental education.Exclusion criteria for both FEP and HC: substance use disorder in the past year based on DSM-5 criteria, history of major head injury, significant medical illness, or contraindications to MRI. acquired using a sagittal 3D MP2RAGE1 sequence with TE=2.83 ms, TR=6000 ms, TI=800ms/2700 ms, flip angle=4/5 degrees, matrix=320x320x208, iPAT=3, partial Fourier=6/8, voxel size=0.8x0.8x0.8, and a 3D SA2RAGE2, with TE=0.81 ms, TR=2400 ms, TI=45/1800 ms, flip angle=4o/5o, matrix=320x320x208, iPAT=3, partial Fourier=6/8, voxel size=0.8mmx0.8mmx0.8mm.Voices MINI Inclusion: diagnosis of schizophrenia or schizoaffective disorder.Age: 18-65, fluent in English, Able to provide informed consent.Exclusion: History of significant head injury or neurological disease affecting cognition (such as epilepsy).Current DSM IV alcohol or substance use or dependence; contraindications to MRI (e.g.pacemaker, orbital foreign body, recent surgery/procedure with metallic devices/implants deployed); currently pregnant 3T Siemens Tim Trio Images were optimized using a magnetization-prepared rapid acquisition gradient echo (MP-RAGE) sequence, and consisted of 176 sagittal slices/brain of 1 mm thickness without gap; field of view = 256 × 256 mm2; repetition time/echo time =1900/2.52ms; data matrix size =256 × 256; voxeldimensions =1.0 × 1.0 ×1.0 mm3.All scans were conducted at a single site.randomly drawn from the national population registry in the same geographical area as the patients, and invited by letter to participate.They were screened prior to participation.Absence of current or previous history of a psychiatric disorder was determined by selfreport.Current symptomatology was screened for on the day of inclusion using the Prime MD and alcohol and drug use were screened for using AUDIT/DUDIT.The exclusion criteria for healthy controls were: -Age outside of the range 18-65 years.-Current or previous psychiatric disorder.-History of severe mental illness in a first-degree relative.-Any alcohol or drug abuse or dependence 1.5T Siemens Magnetom Sonata Two sagittal T1-weighted magnetization prepared rapid gradient echo (MPRAGE) volumes were acquired with the Siemens tfl3d1_ns pulse sequence (TE = 3.93 ms, TR = 2730 ms, TI = 1000 ms, flip angle = 7°; FOV = 24 cm, voxel size= 1.33 x 0.94 x 1 mm3, number of partitions = 160).were Mandarin-speaking Han Chinese individuals from Shanghai metropolitan area.The FES patients were identified according to DSM-IV criteria by qualified psychiatrists using all available clinical information including a diagnostic interview of patients and their family, clinical case notes, and clinician's observations.All healthy subjects were assessed in accordance with DSM-IV criteria as being free of schizophrenia and other axis I disorders, and none had neurological diseases, head trauma, or substance abuse.All participants were right-handed; had no history of substance abuse or suicidal ideation; and had no MRI contraindications.GE Sigma 3T GE Sigma 3.0 T MR (GE Medical Systems, Milwaukee, Wisconsin).TR = 7.8 ms; TE = 3.65 ms; flip angle = 7°; matrix = 256×256; voxel size = were as follows: (1) brain trauma, substance-related disorders, major medical or neurologic disorders; (2) other mental disorders meeting DSM-IV criteria; (3) drug or alcohol abuse; (4) pregnancy, breastfeeding or other unstable clinical state including aggressive behaviour; (5) history of electroconvulsive therapy or transcranial magnetic stimulation within six months; and (6) other contraindications to MRI scanning.To eliminate potential familial effects, healthy subjects whose first-or second-degree relatives had a history of mental disorders were also excluded.3T Siemens MR B17 A 3-Tesla MRI scanner (Siemens MR B17) was used to acquire data in the Shanghai Mental Health Centre.High-spatial-resolution T1-weighted images were collected by a magnetization-prepared rapid acquisition gradient echo (MPRAGE) sequence.The main parameters included repetition time/echo time, 2530/2.56msec; flip angle, 7°; field of view, 256 × 256 mm2; matrix size, 256 × 256; section thickness, 1 mm (no gap); and voxel size, Inpatients with schizophrenia were recruited from the Shanghai Mental Health Center (SMHC).All the patients were recruited from October 2013 to January 2015.All patients met criteria for schizophrenia or schizoaffective disorder based on the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (DSM-IVTR) as conducted by senior psychiatrists.The severity of psychotic symptoms was assessed by the Positive and Negative Syndrome Scale (PANSS).All patients had a total PANSS score of 60 or more and had not received ECT during the past six months.All health controls did not have a lifetime psychiatric disorder or family history of psychosis in their first-degree relatives.Participants were excluded if they had brain injuries, organic mental disorders, neurologic abnormalities, other serious physical illnesses, dementia, substance abuse or dependence, or contraindications to MRI. 3-T Siemens Magnetom Verio Syngo MR B17 High-resolution T1-weighted images were acquired using a 3-T Siemens Magnetom Verio Syngo MR B17 scanner.High-resolution T1-weighted images were collected with a magnetization-prepared rapid acquisition gradient echo (MPRAGE) sequence (TR = 2530 ms; TE = 2.56 ms; flip angle = 7°; inversion time = 1100 ms; FOV = 256 mm × 256 mm; matrix = 256 × 256; slice thickness = 1 mm; 224 slices; and voxel size = 1.0 × 1.0 × 1.0 mm).CN-Harbin DCM-IV SCID Patient recruitment criterion was based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition and Structured Clinical Interview for DSM (SCID), which includes: (1) Age range between 14-45 years old; (2) Intelligence quotient (IQ)>69; (3) The first onset and no systematic antipsychotic treatment before admission; (4) Psychotic symptom assessment scale (positive and negative symptom scale score) is greater than or equal to 60; clinical overall impression CGI severity is greater than or equal to 4 points; (5) Exclude other Axis I mental disorders except schizophrenia, and have no DSM-5 drug or alcohol dependence within the past three months.Exclusion criteria for patients included the following: (1) Sensory-motor disturbances (hearing impairment, blindness), neurological disorders (brain injury, epilepsy), or other medical conditions (2) claustrophobic and unable to undergo MRI scans; (3) patients with repetitive transcranial magnetic stimulation or MRI Contraindications to scanning, such as those with metal implants in the body; (4) suicide attempters, pregnant or breastfeeding women.3.0 Tesla GE Discovery MR750 All scans were acquired on the same 3.0 Tesla GE Discovery MR750 scanner equipped with a 32-channel head coil.CN-Chengdu DSM-IV Patients with SZ were recruited from the Clinical Hospital of Chengdu Brain Science Institute.Each patient was diagnosed based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).Subjects with a history of brain injuries, substance-related disorders, major medical or neurological disorder were excluded.To exclude the potential effect of similar genetic backgrounds, the history of psychiatric disorder in a first-or second-degree relative was an additional exclusion criterion for healthy controls.3-Tesla GE DISCOVERY MR 750 A 3-Tesla MRI scanner (GE DISCOVERY MR 750, USA) was used to collect imaging data in the University of Electronic Science and Technology of China.High-resolution T1-weighted images were acquired using a three dimensional fast spoiled gradient echo (T1-3D FSPGR) sequence.The main parameters include: TR = 6.008 ms; TE = 1.984 ms; flip angle (FA) =90°; field of view (FOV) = 25.6 cm × 25.6 cm; matrix size = 256 × 256; slice thickness = 1 mm (no gap).CN-Taibei DSM-IV Patients and matched healthy controls were recruited from the Veteran General Hospital in Taipei, Taiwan.All participants were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorder-IV criteria for schizophrenia, and each participant's history of medical disease, psychiatric illness, and medication use was evaluated by interview and medical charts carefully.Any participants with the following conditions were excluded: (1) a comorbid substance-related disorder, (2) presence of neurobiological disorders, such as dementia, head injury, stroke, or Parkinson's disease; (3) presence of hypertension, diabetes, hyperlipidemia or coronary heart disease; (4) severe medical illness, such as malignancy, heart failure, or renal failure; (4) presence of ferromagnetic foreign bodies or implants that were anywhere in the body.3T Siemens Siemens MAGNETOM Tim Trio 3.0T MRI Scanner (Siemens Healthcare, Erlangen, Germany) with a 12-channel head coil, using 3-dimensional magnetization prepared rapid gradient-echo sequence.TR: 2530 ms, TE: 3.5 ms, TI: 1,100 ms, FoV: 256 mm, flip angle: 7 degree, 192 sagittal slices, voxel size = 1.0 mm3 cubic, no gap.CN-Zhengzhou DSM-IV All patients were identified according to the Diagnosis and Statistic Manual of Mental Disorders, fourth edition (DSM-IV) criteria for schizophrenia by qualified psychiatrists using all available clinical information including a diagnostic interview, clinical case notes, and clinician's observations.The severity of positive and negative symptoms was assessed by trained and experienced psychiatrists using PANSS scoring.Individuals were excluded from the study if they were diagnosed with GE MR750 3T GE MR750 3T MRI scanner with standard quadrature head coil.TR/TE= 8.2 / 3.2 ms, FOV= 256×256 mm 2, Matrix= 256×256, slice thickness= 1.0 mm, gap= 0mm, 188 contiguous sagittal slices；flip angle = 12°.schizoaffective disorder, mood disorders, other cognitive disorders, epilepsy, had severe physical diseases, alcohol/drug dependence, or been treated with electroconvulsive therapy.Healthy subjects were assessed in accordance with DSM-IV criteria as being free of schizophrenia and other Axis I disorder, and none had neurological diseases, head trauma, substance abuse, suicidal ideation, and MRI contraindications.CN-Beijing1 DSM-IV The inclusion criteria were: (1) both in-and out-patients, (2) both genders, (3) diagnosis of schizophrenia established with Structured Clinical Interview for the DSM-IV Axis I Disorder, patient edition, (4) aged between 18 and 45 years, (5) onset at age ≥ 15 years, (6) first episode of schizophrenia, (7) no previous psychiatric treatment ('drug-naïve' status), and (8) ability to understand the contents of interview and provide written informed consent.The exclusion criteria were: (1) a history or diagnosis of major medical conditions, (2) a history of alcohol and / or drug abuse or dependence, and (3) contra-indication to olanzapine, aripiprazole, or risperidone.parameters: TR: 9.8 ms, TE: 3.8 ms, TI: 450 ms, FoV: 512 x 512, flip angle: 13, slice thickness=1.2mm.CN-Beijing2 DSM-IV A consensus diagnosis of schizophrenia was made by two experienced senior psychiatrists according to the Diagnosis and Statistic Manual of Mental Disorders, fourth edition (DSM-IV) criteria for schizophrenia or schizophreniform disorder using the Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Patient Edition (SCID-I/P).All subjects initially recruited with schizophreniform disorder were finally diagnosed with schizophrenia after being followed up for at least six months.Individuals were excluded from the study if they were diagnosed with schizoaffective disorder, mood disorders, delusional disorder, brief psychotic disorder, psychosis associated with substance use or medical conditions, learning disability, pervasive developmental disorder, delirium, dementia, amnesia or other cognitive disorders; had severe, unstable physical diseases (such as diabetes, thyroid diseases, hypertension and cardiac diseases), a well-documented history of epilepsy, a DSM-IV diagnosis of alcohol or drug dependence; had been treated with electroconvulsive therapy within the last six months; were pregnant or breastfeeding; had previously attempted suicide; or had experienced symptoms of severe excitement and agitation within one week before MRI scanning.Healthy control individuals were recruited from each hospital and screened using SCID-I, Non-Patient Edition (SCID-I/NP).Individuals with any history of mental disorders or first-or second-degree relatives with any history of mental disorders were excluded.Siemens Trio Trim 3.0 T T1-weighted images were collected with matrix size of 256×256, resolution of 1×1 mm2, and slice thickness of 1 mm.CN-Changsha DSM-IV SCID-P The inclusion/exclusion criteria of patients: (1) diagnosis of SCZ confirmed using the Structured Clinical Interview for DSM-IV-patient version (SCID-P) 1; (2) Han Chinese ethnicity and righthanded; (3) minimum 9 years of school education (4) good general physical health with no known Philips Gyroscan Achieva 3T 3-D structural MRI images (T1-weighted) were acquired from the sagittal plane using spoiled gradient echo (SPGR) pulse sequence on a Philips Gyroscan Achieva 3T MRI scanner, scanning parameter: TR=12 ms, endocrine, metabolic or inflammatory disorders; (5) no known neurological disorder; (6) no substance dependence in the last year; (7) benzodiazepine treatment, if any, stopped more than 24 h prior to scanning and (8) no contraindications for MRI.

TE=4. 2
ms, flip angle=15°, 172 slices, matrix size=256×256, and the field of view (FOV)=24×24 cm2.CN-Xian DSM-IV, DSM-V Inclusion criteria were the following: (1) diagnosis of schizophrenia using the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (SCID-IV), (2)patients were taking stable doses of antipsychotic medication for at least 8 weeks before the study;(3) no history of significant head trauma or neurological disorders and no focal brain lesions by T1or T2-weighted MRI; (4) no alcohol or drug abuse; and (5) patient has no recent aggression or other forms of behavioral dysfunction.GE Discovery MR750 3.0 T High-resolution T1-weighted MRI was acquired using a GE Discovery MR750 3.0 T scanner located in the Department of Radiology, and all subjects underwent T2WI scans to rule out organic diseases.The scanning parameters were repetition time 8.2 ms, echo time 3.2 ms, flip angle 12°, field of view 256 × 256 mm, matrix 256 × 256, slice thickness 1 mm, and sagittal slices 196.HCP-EP DSM-V Available at https://www.humanconnectome.org/study/human-connectome-project-for-early-psychosisJP-SRPBS Available at https://bicr-resource.atr.jp/srpbsfc/fBIRN SCID DSM-IV-TR All subjects diagnosed with schizophrenia were clinically stable outpatients whose antipsychotic medications and doses had not changed within the last two months.Schizophrenia and healthy volunteers with a history of major medical illness, drug dependence in the last five years (except for nicotine), current substance abuse disorder, or MRI contraindications, were excluded.Individuals with schizophrenia who had significant tardive dyskinesia and healthy volunteers with a current or past history of major neurological or psychiatric illness or with a first-degree relative with a DSM IV Axis-I psychotic disorder diagnosis were also excluded.3T Siemens Tim Trio; 3T GE High-resolution structural imaging scans were acquired on six 3T Siemens Tim® Trio System and one 3T General Electric Discovery MR750 scanner.MP-RAGE scan parameters for the Siemens scanner were: scan plane=sagittal, TR/TE/TI=2300/2.94/1100ms,GRAPPA acceleration factor=2, flip angle=9°, resolution=256×256x160, FOV=220mm2, voxel size=0.86x0.86x1.2mm,and NEX=1.IR-SPGR scan parameters for the General Electric scanner were: scan plane=sagittal, TR/TE/TI=5.95/1.99/450ms,ASSET acceleration factor=2, a flip angle=12°, resolution=256×256x166, FOV=220mm2, voxel size=0.86x0.86x1.2mm,andNEX=1.All scans covered the entire brain.between the ages of 18 and 60 and spoke English as their native language.To be included in the schizophrenia cohort, patients had to meet diagnostic criteria for schizophrenia, schizoaffective disorder, or schizophreniform disorder.Concerted effort was made to recruit patients early in the course of their illness and especially those who were antipsychotic drug naï ve.The healthy control subjects with no current or past history of psychiatric illness including substance abuse or dependence were matched within site to the patient cohort for age, sex, and parental education.Control subjects who had not been diagnosed with any psychiatric disorders, but had been medicated with antidepressants, anti-anxiety medication or medication for sleep disturbance 1.5, 3T Siemens and GE T1 scans: TR = 2530 ms for 3 T, TR = 12 ms for 1.5 T; TE = 3.79 ms for 3 T, TE = 4.76 ms for 1.5 T; FA = 7 for 3 T, FA = 20 for 1.5 T; TI = 1100 for 3 T; Bandwidth = 181 for 3 T, Bandwidth = 110 for 1.5 T; 0.625×0.625mm voxel size; slice thickness 1.5 mm; FOV 256×256×128 cm matrix; FOV = 16 cm was acquired using a sagittal MP-RAGE 3D sequence (TR = 2400 ms, TE = 3.16 ms, flip = 8°; voxel size = 1 mm × 1 mm × 1 mm).DS004302 DSM-V Patients meeting DSM-5 criteria for schizophrenia were initially recruited from four psychiatric hospitals in Barcelona.Diagnoses were made using the Structured Clinical Interview for DSM Disorders (SCID).Patients were excluded if they (a) were younger than 18 or older than 65, (b) had a history of brain trauma or neurological disease or (c) had shown alcohol/substance abuse/dependence within 12 months prior to participation.Social use of alcohol was permitted, as was non-habitual use of cannabis.Electroconvulsive therapy in the past 6 months was also an exclusion criterion.All participants were right-handed and were taking antipsychotic medication.

Table 2 . Dataset-specific information. Cohort Diagnosis measurement Exclusion/inclusion criteria Scanner manufacturer and type Imaging protocols
Early or first-episode psychosis, Czech language as a mother tongue, 18-60 years old.Neurocognitive disorders (organic mental disorder), mental disorders caused by addiction, mental retardation (IQ<80), severe neurological disorder, head injury, hypertension, cerebrovascular disease, epilepsy, migraine, endocrine disorders.Patients had a diagnosis of schizophrenia.All participants were in the 18-65 age range.Controls were excluded if they reported a history of mental illness and/or treatment with psychotropic medication.Patients were excluded if have had a history of brain trauma or neurological disease or had shown alcohol/ substance abuse within 12 months before participation 1.5T GE Signa 180 axial slices; 1mm slice thickness, no gap, matrix size 512x512; 0.5x0.5x1mm3voxelresolution; TE 4ms, TR 2000ms, flip angle 15. structured interview All participatnts were in the 18-65 age range; patients were diagnosed of schizophrenia, schizoaffective disorder or any schizophreniform disorder.Exclusion criteria all: any history of neurological (head trauma or unconsciousness) and medical condition (severe somatic disorders), IQ<80; Exclusion criteria controls: any current or former psychiatric disorder; Exclusion criteria patients: Current benzodiazepine treatment (wash out of at least three half-lives before study participation).3TSiemens Magnetom TrioTim Syngo MPRAGE imaging sequence.1 acquisition.Flip angle: 9 degrees.TE: 2.26 ms.TR: 1900 ms.TI: 900 ms.Acceleration factor: 2Field of view: 256.IQ<80; Exclusion criteria controls: any current or former psychiatric disorder; Exclusion criteria patients: Current benzodiazepine treatment (wash out of at least three half-lives before study participation).Head coil; 3D-IR-FSPGR, TR/TE/TI=7.2/2.9/400ms,flipangle=11°, 256x256x172 matrix, FOV=240x240mm, slice thickness=1.0mm,Nex=1,No Asset, 8ch Brain coil.PENS DSM-IV Same as PHCP study: Adults aged 18-65, including people with major mental illness (schizophrenia, schizoaffective disorder, bipolar I disorder with psychotic features), their first-degree biological relatives, and unrelated healthy controls.All participants spoke English as their primary language and did not have: a legal guardian (or otherwise lack capacity to provide informed consent), alcohol/drug abuse in the past month or Each of the patient groups (Schizophrenia, Bipolar Disorder, and ADHD) excluded anyone with one of these other diagnoses; stable medications were permitted for the patients.For MRI studies we excluded participants who were left handed, who believed they might be pregnant, or had other contraindications to scanning (e.g., claustrophobia, metal in body, body too large to fit in NUSDASTThe Northwestern University Schizophrenia Data and Software Tool (NUSDAST) is a repository of schizophrenia neuroimaging data collected from over 450 individuals with schizophrenia, healthy controls and their respective siblings, most with 2-year longitudinal follow-up.More details are provided at: Wang L, Kogan A, Cobia D, et al.Northwestern University schizophrenia data and software tool (NUSDAST).Frontiers in neuroinformatics, 2013, 7: 25. using Adult ADHD Interview; healthy participants were screened for sub-threshold ADHD, defined as 4 or more ADHD inattentive or hyperactive/impulsive symptoms in either childhood and adulthood; in addition, they could not have had medication treatment for ADHD within the prior 12 clinically unstable or severe medical disorder; (c) had a history of head injury with documented neurological sequelae or loss of consciousness; or (d) met DSM-IV criteria for mental retardation.

Table 5 . Morphological z-scores of all brain regions and inter-subtype comparisons.
Note: * two-sided p<0.05 (derived from two sample t test) after Family Wise Error (FWE) correction.